Project Summary/Abstract Regulatory T cells (Tregs) play a major role in establishing and maintaining immune homeostasis. However, an emerging body of work suggests that these cells have `specialized' functions in tissues in addition to their role as immune regulatory cells. We have discovered that Tregs in skin play a critical role in regulating fibroblast activation and dermal fibrosis in both mouse and humanized mouse models. In addition, we have generated a novel protein that selectively activates Tregs in vivo. The underlying theme of this proposal is to functionally dissect the dominant cellular and molecular mechanisms utilized by Tregs in skin to influence fibroblast function. We will also discern whether in vivo activation of Tregs results in a diminution of skin fibrosis. The experiments outlined herein represent a conceptually and technically innovative, systematic approach to better understand how Tregs influence the biology of skin fibroblasts. In doing so, we will undercover a critical mechanistic link between two skin-resident cell populations with clear and evident impact on tissue function. Our results may have direct implications for wound healing and/or chronic fibrosing diseases, with the possibility of uncovering a new therapeutic strategy for these conditions.